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1.
bioRxiv ; 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39149244

RESUMO

Natural Killer (NK) cells utilize effector functions, including antibody-dependent cellular cytotoxicity (ADCC), for the clearance of viral infection and cellular malignancies. NK cell ADCC is mediated by Fc γ RIIIa (CD16a) binding to the fragment crystallizable (Fc) region of immunoglobulin G (IgG) within immune complexes on a target cell surface. While antibody-induced clustering of CD16a is thought to drive ADCC, the molecular basis for this activity has not been fully described. Here we use MINFLUX nanoscopy to map the spatial distribution of stoichiometrically labeled CD16a across the NK cell membrane, revealing the presence of pairs of CD16a molecules with intra-doublet distance of approximately 17 nm. NK cells activated on supported lipid bilayers by Trastuzumab results in an increase of synaptic regions with greater CD16a density. Our results provide the highest spatial resolution yet described for CD16a imaging, offering new insight into how CD16a organization within the immune synapse could influence ADCC activity. MINFLUX holds great promise to further unravel the molecular details driving CD16a-based activation of NK cells.

2.
J Immunol ; 213(1): 40-51, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38809096

RESUMO

NK cells are innate immune effectors that kill virally infected or malignant cells. NK cell deficiency (NKD) occurs when NK cell development or function is impaired and variants in MCM4, GINS1, MCM10, and GINS4 result in NKD. Although NK cells are strongly impacted by mutational deficiencies in helicase proteins, the mechanisms underlying this specific susceptibility are poorly understood. In this study, we induced replication stress in activated NK cells or T cells by chemical and genetic methods. We found that the CD56bright subset of NK cells accumulates more DNA damage and replication stress during activation than do CD56dim NK cells or T cells. Aphidicolin treatment increases apoptosis of CD56bright NK cells through increased pan-caspase expression and decreases perforin expression in surviving cells. These findings show that sensitivity to replication stress affects NK cell survival and function and contributes to NKD.


Assuntos
Apoptose , Células Matadoras Naturais , Ativação Linfocitária , Humanos , Células Matadoras Naturais/imunologia , Apoptose/imunologia , Ativação Linfocitária/imunologia , Dano ao DNA , Replicação do DNA , Antígeno CD56/metabolismo , Estresse Fisiológico/imunologia , Linfócitos T/imunologia , Células Cultivadas
3.
J Clin Invest ; 134(15)2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38805302

RESUMO

The surface receptor CD8α is present on 20%-80% of human (but not mouse) NK cells, yet its function on NK cells remains poorly understood. CD8α expression on donor NK cells was associated with a lack of therapeutic responses in patients with leukemia in prior studies, thus, we hypothesized that CD8α may affect critical NK cell functions. Here, we discovered that CD8α- NK cells had improved control of leukemia in xenograft models compared with CD8α+ NK cells, likely due to an enhanced capacity for proliferation. Unexpectedly, we found that CD8α expression was induced on approximately 30% of previously CD8α- NK cells following IL-15 stimulation. These induced CD8α+ (iCD8α+) NK cells had the greatest proliferation, responses to IL-15 signaling, and metabolic activity compared with those that sustained existing CD8α expression (sustained CD8α+) or those that remained CD8α- (persistent CD8α-). These iCD8α+ cells originated from an IL-15Rßhi NK cell population, with CD8α expression dependent on the transcription factor RUNX3. Moreover, CD8A CRISPR/Cas9 deletion resulted in enhanced responses through the activating receptor NKp30, possibly by modulating KIR inhibitory function. Thus, CD8α status identified human NK cell capacity for IL-15-induced proliferation and metabolism in a time-dependent fashion, and its presence had a suppressive effect on NK cell-activating receptors.


Assuntos
Antígenos CD8 , Proliferação de Células , Interleucina-15 , Células Matadoras Naturais , Ativação Linfocitária , Humanos , Antígenos CD8/metabolismo , Antígenos CD8/imunologia , Antígenos CD8/genética , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-15/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo
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